Estimating and testing direct genetic effects in directed acyclic graphs using estimating equations

In genetic association studies, it is important to distinguish direct and indirect genetic effects in order to build truly functional models. For this purpose, we consider a directed acyclic graph setting with genetic variants, primary and intermediate phenotypes, and confounding factors. In order to make valid statistical inference on direct genetic effects on the primary phenotype, it is necessary to consider all potential effects in the graph, and we propose to use the estimating equations method with robust Huber-White sandwich standard errors. We evaluate the proposed causal inference based on estimating equations (CIEE) method and compare it with traditional multiple regression methods, the structural equation modeling method, and sequential G-estimation methods through a simulation study for the analysis of (completely observed) quantitative traits and time-to-event traits subject to censoring as primary phenotypes. The results show that CIEE provides valid estimators and inference by successfully removing the effect of intermediate phenotypes from the primary phenotype and is robust against measured and unmeasured confounding of the indirect effect through observed factors. All other methods except the sequential G-estimation method for quantitative traits fail in some scenarios where their test statistics yield inflated type I errors. In the analysis of the Genetic Analysis Workshop 19 dataset, we estimate and test genetic effects on blood pressure accounting for intermediate gene expression phenotypes. The results show that CIEE can identify genetic variants that would be missed by traditional regression analyses. CIEE is computationally fast, widely applicable to different fields, and available as an R package

Fractional Loop Group and Twisted K-Theory

We study the structure of abelian extensions of the group $L_qG$ of $q$-differentiable loops (in the Sobolev sense), generalizing from the case of central extension of the smooth loop group. This is motivated by the aim of understanding the problems with current algebras in higher dimensions. Highest weight modules are constructed for the Lie algebra. The construction is extended to the current algebra of supersymmetric Wess-Zumino-Witten model. An application to the twisted K-theory on $G$ is discussed.Comment: Final version in Commun. Math. Phy

Schwinger Terms and Cohomology of Pseudodifferential Operators

We study the cohomology of the Schwinger term arising in second quantization of the class of observables belonging to the restricted general linear algebra. We prove that, for all pseudodifferential operators in 3+1 dimensions of this type, the Schwinger term is equivalent to the ``twisted'' Radul cocycle, a modified version of the Radul cocycle arising in non-commutative differential geometry. In the process we also show how the ordinary Radul cocycle for any pair of pseudodifferential operators in any dimension can be written as the phase space integral of the star commutator of their symbols projected to the appropriate asymptotic component.Comment: 19 pages, plain te

I Blame Therefore it Was: Rape Myth Acceptance, Victim Blaming, and Memory Reconstruction

We examined the causal order of relationships between rape myth acceptance (RMA), victim blaming, and memory reconstruction. In Study 1, RMA-congruent memory (or alternatively, victim blaming) mediated the relationship between RMA and victim blaming (memory reconstruction). In Study 2, similar relationships emerged between RMA, victim blaming, and memory reconstruction. Although no mediation of RMA occurred in Study 2 independently, a mini meta-analysis of Studies 1 and 2 data replicated both patterns of mediation observed in Study 1. In Study 3, memory accuracy for neutral details of a rape scenario was unrelated to RMA. Manipulating memory to be more (vs. less) RMA congruent had no effect on victim blaming (Study 4), although manipulating perceived victim blameworthiness (Studies 5 and 6) produced RMA-congruent memory reconstruction when the victim was more (vs. less) blameworthy. The results suggest that, via victim blaming, RMA motivates a memory reconstruction process that explains and justifies victim blaming after the fact

Exon-Specific QTLs Skew the Inferred Distribution of Expression QTLs Detected Using Gene Expression Array Data

Mapping of expression quantitative trait loci (eQTLs) is an important technique for studying how genetic variation affects gene regulation in natural populations. In a previous study using Illumina expression data from human lymphoblastoid cell lines, we reported that cis-eQTLs are especially enriched around transcription start sites (TSSs) and immediately upstream of transcription end sites (TESs). In this paper, we revisit the distribution of eQTLs using additional data from Affymetrix exon arrays and from RNA sequencing. We confirm that most eQTLs lie close to the target genes; that transcribed regions are generally enriched for eQTLs; that eQTLs are more abundant in exons than introns; and that the peak density of eQTLs occurs at the TSS. However, we find that the intriguing TES peak is greatly reduced or absent in the Affymetrix and RNA-seq data. Instead our data suggest that the TES peak observed in the Illumina data is mainly due to exon-specific QTLs that affect 3′ untranslated regions, where most of the Illumina probes are positioned. Nonetheless, we do observe an overall enrichment of eQTLs in exons versus introns in all three data sets, consistent with an important role for exonic sequences in gene regulation

Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.

One fundamental but understudied mechanism of gene regulation in disease is allele-specific expression (ASE), the preferential expression of one allele. We leveraged RNA-sequencing data from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box small nucleolar RNAs (snoRNAs), are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA-targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Origins of cattle on Chirikof Island, Alaska, elucidated from genome-wide SNP genotypes

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Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

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